P1375: VENETOCLAX MODULATES TIM-3 EXPRESSION ON CD8 T CELLS IN ACUTE MYELOID LEUKEMIA PATIENTS
Authors: Darina Ocadlikova, Giulia Corradi, Dorian Forte, Gianluca Cristiano, Michele Cavo, Antonio Curti
Journal: HemaSphere (2023)

Topic: 24. Gene therapy, cellular immunotherapy and vaccination - Biology & Translational Research Background: The targeting of the anti-apoptotic B-cell lymphoma 2 (BCL-2) pathway has emerged as an efficacious and well-tolerated clinical strategy in acute myeloide leukemia (AML). In particular, Venetoclax (VEN), a specific BCL-2 inhibitor, showed remarkable results in combination with hypomethylating agents (HMAs) and low-dose cytarabine, leading to the approval for the treatment of newly diagnosed unfit-for-chemotherapy AML patients. Although the mechanisms have been well established, few studies analyzed the effect of VEN treatment on immune cells in AML. Aims: In this study, we aimed to better characterize the immunological milieu of AML patients treated with VEN in combination with HMAs, by focusing on the expression dynamics of immune checkpoint receptors before and after treatment. Methods: PB from 12 patients with AML before treatment, 18 patients after 1 cycle of HMAs+VEN and 12 patients after 2 cycles of HMAs+VEN were collected. As a control group, 4 patients treated only with HMAs were analyzed. Multi-parametric flow-cytometry was used to provide an extensive characterization of T cells from peripheral blood (PB) at baseline, and after treatment. Results: To evaluate the effects of HMAs+VEN treatment on circulating immune cell repertoire, we first analyzed CD4+ and CD8+ T cell subsets in the PB of AML patients during treatment compared to baseline. Our data suggest that combining HMAs+VEN treatment can induce a redistribution of immune cell subsets towards a more naïve phenotype for CD8+ T-cell subsets. In contrast, no significant changes in T regulatory compartment were observed, while a decrease of non-suppressive T cells secreting cytokines was shown. We then evaluated the effects of HMAs+VEN treatment on the expression of both inhibitory and activatory immune checkpoint receptors. Our data revealed a significant Tim-3 up-regulation on CD8+ T cells and a trend towards PD-1 and PD-1/Tim-3 down-regulation on both CD4+ and CD8+ T cells. On the contrary, the treatment does not influence the expression of immune checkpoints on T regulatory cells. To understand the specific contribution of VEN in modulating the immune cell repertoire of AML patients treated with HMAs+VEN, we considered only pair-matched patients for each time points and we highlighted the crucial role of VEN in modulating the expression of inhibitory immune checkpoint receptors on T cells. In particular, the increased expression of TIM-3 on CD8+ T cells and the decreased of double PD-1/Tim-3 positive CD4+ and CD8+ T cells is specifically induced by VEN. Summary/Conclusion: Our data suggest that VEN modulates expression of Tim-3 on CD8+ T cells in AML. The results of this study will be correlated with patients’ clinical outcomes to evaluate the immune system’s role in determining the therapy response or resistance to VEN treatment in AML patients. Understanding the immunological microenvironment under the action of selective BCL-2 inhibition can potentially reveal both novel mechanisms of resistance and new treatment combinations. Keywords: Venetoclax, Acute myeloid leukemia